This invention relates to novel, antitumor organoplatinum complexes. More particularly, the invention relates to amino-substituted malonato platinum(II) complexes having water solubility and a high antitumor activity, and a method for their preparation.
An important requirement for an effective treatment of animal tumors with anticancer platinum complexes is still a high solubility in aqueous fluids for intravenous injection. In the last several years an extensive number of cis-dichlorodiamineplatinum (cis-DDP) analogs have been synthesized. Several of these second generation cis-DDP complexes are of general formula L.sub.2 Pt.sup.II X.sub.2, wherein L or L.sub.2 are neutral monodentate or bidentate amine ligands respectively, and X.sup.- or X.sub.2.sup.= are anionic monodentate or bidentate ligands respectively. In order to increase the water solubility and, therefore, the clinical potentiality of these organoplatinum compounds, several authors have suggested the use of neutral or anionic ligands having polar or hydrophilic substituents. For example, Hydes et al. (U.S. Pat. No. 4,203,912; U.S. Pat. No. 4,225,529 and U.S. Pat. No. 4,230,631) and Cleare et al. (U.S. Pat. No. 4,140,707) have reported the use of polar substituents (such as halogen, hydroxy, amino, carboxylic acid groups etc.) in the L or L.sub.2 amine ligands; i.e., in the ligands which are coordinated to the platinum through a nitrogen atom. Alternatively, these inventors have reported the use of polar substituents, such as the above-cited groups, attached to the anionic ligands, but the latter being of the monodentate type, i.e., substituted-monocarboxylates. In this case, the presence of polar groups has indeed increased the water solubility of the platinum compounds. However, the use of monodentate anionic ligands, such as monocarboxylates, or of anionic ligands, such as 1/2SO.sub.4.sup.=, NO.sub.3.sup.-, OH.sup.- (Gale et al., U.S. Pat. No. 4,115,418), led to kinetically reactive species, which rapidly undergo hydrolysis and, consequently, appear highly toxic in vivo (M. E. Howe-Grant and S. J. Lippard, "Metal Ions in Biological Systems", Vol. 11, page 63, Ed. H. Sigel, New York and Basel, 1980). On the other hand the use of cyclic carboxylate ions, such as oxalate, malonate or substitued malonates, has originated compounds with increased chemical stability, in addition to havine a good antitumor activity (M. J. Cleare and P. C. Hydes in "Metal Ions in Biological Systems", Vol. 11, page 1, Ed. H. Sigel, New York and Basel, 1980). The stability of these organoplatinum species has been attributed to the chelate effect of the dicarboxylato ligand, the chelate effect being maximum for a 5 or 6 membered ring as in the case of oxalate and malonate derivatives respectively. In order to increase their water solubility, Hydes et al. (U.S. Pat. No. 4,203,912; U.S. Pat. No. 4,225,529 and U.S. Pat. No. 4,230,631) and Cleare et al. (U.S. Pat. No. 4,140,707) have reported substituents attached in position 2 of the malonato ligands, but of low hydrophilicity, such as halogen, hydroxy or nitro groups. The use of a substituent of high hydrophilic character, such as a free amino group, has never been specified so far. This may be due also to the difficulty in the synthesis of such compounds.
It was conceived by the inventor to obtain structurally different malonato platinum(II) complexes, i.e., with a high hydrophilic group in position 2 of the chelating dicarboxylate, which will lead to a new class of very potent antitumor agents having chemical stability (the chelating effect of a 6 membered ring being provided by the anionic bidentate ligand), together with a high water solubility for intravenous administration.
It is, therefore, an object of the present invention to provide new malonato platinum complexes, having high antitumor properties at non-toxic doses. It is another object of the present invention to provide new malonato platinum complexes, which contain a high hydrophilic group for increased solubility in aqueous fluids for intravenous administration in the treatment of animal tumors.
Thus the invention consists in novel amino-substituted malonato platinum(II) complexes having the general formula: EQU L.sub.2 Pt.sup.II (OCO).sub.2 CH--NH.sub.2
wherein: L and L.sub.2 are aliphatic amine ligands as hereinafter defined:
L is a monodentate ligand of the type HNRR.sup.1 or an aminoacid, coordinated to the platinum through an N atom, such that the platinum is in the +2 oxidation state, wherein, when R=H, R.sup.1 can be selected from the group consisting of hydrogen, hydroxy (e.g., hydroxylamine), substituted or unsubstituted straight- or branched-chain lower alkyl (e.g., methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-amines etc.), cycloalkyl (e.g., cyclopropyl-, cyclohexyl-amines etc.), hydroxy lower alkyl (e.g., hydroxyethyl-, hydroxypropyl-amines etc.), lower alkoxy (e.g., methoxylamine etc.), alkoxyalkylamines (e.g., methoxy-methylamine etc.), carboxylic acid (e.g., alanine etc.); R and R.sup.1 can also be combined with the N atom to form an heterocyclic group (e.g., ethylenimine). It is to be understood that the organoplatinum compounds of the invention may include two identical or different monodentate amine ligands.
L.sub.2 is a bidentate ligand of the type HNR.sup.2 --CHR.sup.3 --(CR.sup.4 R.sup.5).sub.n --CHR.sup.6 --NHR.sup.7, wherein n=0 or 1, and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 are the same or different substituents and can be selected from the group consisting of H, hydroxyl, lower alkyl (e.g., methyl, ethyl), lower alkoxy (e.g., methoxy, ethoxy), cycloalkyl (e.g., cyclohexyl); when n=0, R.sup.3 and R.sup.6 can be combined through methylene or substituted methylene groups to form a cycloalkyl group (e.g., 1,2-diaminocyclohexane); when n=1, R.sup.3 and R.sup.4 can be combined in a similar way to form a cycloalkyl group (e.g., 1-aminomethyl-2-aminocyclohexane) or R.sup.4 and R.sup.5 can be combined with carbon 2 of the 1,3-diaminopropane skeleton to form a cycloalkyl group (e.g., 1,1-bisaminomethyl-cyclohexane).
It is suggested that, when choosing the amine ligands (either of the monodentate or bidentate type) for the preparation of the organoplatinum complexes in accordance with this invention, the ligands should contain a limited number of alkyl or cycloalkyl substituents; that is, in order not to increase the hydrophobicity of the final compound. For example, in the case of L=HNRR.sup.1, R is preferably H and R.sup.1 can be selected from a lower alkyl or cycloalkyl group. Similarly, when L.sub.2 =HNR.sup.2 --CHR.sup.3 --(CR.sup.4 R.sup.5).sub.n --CHR.sup.6 --NHR.sup.7, R.sup.2 and R.sup.7 are preferably H, as also some of the R.sup.3, R.sup.4, R.sup.6 groups.
Some typical examples of water-soluble amino-substitued malonato platinum(II) complexes included in the above general formula, without being limited thereto, are represented below:
______________________________________ ##STR1## AM-DP: [amino- malonate(diamine) platinum(II)]. ##STR2## AM-EP: [amino- malonate(ethylen- diamine)plati- num(II)]. ##STR3## AM-DACHP: [aminomalonate (1,2-diaminocyclo- hexane)plati- num(II)]. ##STR4## AM-AZP: [aminomalonate (diethylenimine) platinum(I I)]. ##STR5## AM-CPRP: [aminomalonate (dicyclopropyl- amine)plat i- num(II)]. ##STR6## AM-CBP: [amino- malonate(dicyclo- butylamine)plati - num(II)]. ##STR7## AM-CPP: [amino- malonate(dicyclo- pentylamine)plat i- num(II)]. ##STR8## AM-CHP: [aminomalonate (dicyclohexyl- amine)plati- num(II)]. ##STR9## AM-IPA: [amino- malonate(diiso- propylamine)plati- num(II)]. ##STR10## AM-NPA: [aminomalonate (di n-propylamine) platinum(II)]. ______________________________________
In addition to the chemical stability characteristic of platinum(II) compounds of the malonato type, the presence of a free amino group in position 2 of the malonato ligand provides a high solubility in aqueous fluids for intravenous (i.v.) administration, the solubility in water being in the range of 40 mg/ml at room temperature. Moreover, the compounds of this invention are characterized by a potent antitumor activity against malignant tumors in vivo, such as PIR-2 lymphoma, advanced L 1210 leukemia and B 16 melanoma. The experiments, hereinafter described, will illustrate the high chemotherpeutic potentiality of some representative compounds in accordance with this invention for the treatment of animal tumors. The activities are evaluated as %T/C (i.e., median survival time of treated mice divided by median survival time of untreated mice expressed as a percentage). In all the experiments, seven to ten mice were employed in a control group, and four to seven mice were employed in a test group.